RU1837876C - Method for applying coating on antibiotics - Google Patents

Abstract

Usage: the invention relates to medicine, namely to the pharmaceutical industry, and relates to a method for coating an antibiotic. The aim of the invention is to increase the absorption of the target product in the gastrointestinal tract. The invention consists in dispersing the cefuroxime axetil antibiotic in an amount of 5 to 20% of the total weight of the dispersion in molten wax, with a melting point of 30 to 80 ° C, and the dispersion is carried out in an atomizer with a pneumatic nozzle at a temperature of 10-20 ° ; deg; C above the melting point of the wax, whereby particles with a diameter of 20-100 microns are obtained. The beneficial effect is to mask the bitter taste while increasing absorption. 5 cp crystals, 4 tab.

Description

The invention relates to medicine, namely to the pharmaceutical industry, and relates to a method for coating an antibiotic. The antibiotic used is cefuroximaxetil, cefuroxime, which is a valuable antibiotic with a wide spectrum of action, characterized by high activity against a number of gram-positive and gram-negative microorganisms, and this property is enhanced by the very high stability of this compound to / - Lactamases, produced by a number of gram-negative microorganisms, Cefuroxime and its salts are of particular value as drugs for injections, since they are very poorly absorbed from the gastrointestinal of tract.

The purpose of the invention is to increase absorption in the gastrointestinal tract.

In order to provide flavored masked cefuroxime particles suitable for oral administration, the melting temperature of the lipid used should be high enough to prevent melting of the coated particle in the oral cavity, which would release the bitter active ingredient, but not so high that the active ingredient, cefuroxime axetil, has melted and / or chemically decomposed during the coating process. Thus, the lipid or lipid mixture for use in the present invention should have a melting point of 30-80 ° C, preferably 40-70 ° C. If the composition of the present invention contains amorphous cefuroxime axetil, the melting point of the lipid or lipid mixture of 45-60 ° C is most preferred.

Suitable lipids include fatty acids or their monohydric alcohols, fixed oils, fats, waxes, sterols, phospholipids and glycolipids. Lipid maybe

CA C

00 CL VJ 00 VI O

with

for example, high molecular weight (Skzo) with a normal chain saturated or unsaturated aliphatic acid, such as stearic acid or palmitic acid, triglyceride, for example, a complex of glyceric ester of high molecular weight (do-zo) aliphatic acid, such as glycerol trilaurate or trimirate hydrogenated vegetable oil such as cottonseed or soya bean wax, for example bee or carnauba wax, for example bee or carnauba wax, high molecular weight (do-zo) with normal Strongly aliphatic alcohol such as stearyl or cetyl alcohol, or mixtures thereof. Mixtures of high molecular weight fatty acids such as mixtures of stearic or palmitic acids, mixtures of high molecular weight normal chain aliphatic alcohols such as cetostearyl alcohol, mixtures of partially hydrogenated cottonseed and soybean oils, and mixtures of high molecular weight aliphatic acids and mixtures of high molecular weight aliphatic acids and glycerol esters such as a mixture of stearic acid and trilaurate glycerin. A particularly preferred lipid which provides high bioavailability and has physical properties compatible with cefuroxime acostil is stearic acid mixed with palmitic acid in a weight ratio of (3: 7) to (7: 3), more preferably in a ratio of 1: 1.

The composition of the present invention may contain cefuroxime axetil in crystalline form or more preferably in amorphous form.

If desired, cefuroxime axetil may first be coated with a coating agent. This intermediate coating may serve to protect cefuroxime axetil when it may be chemically sensitive to the lipid with which it is coated.

The coating agent used for the intermediate coating is preferably a water soluble and film forming agent. Useful film-forming agents include polysaccharides such as maltodextrin, alkyl celluloses such as methyl or cellulose acetate, hydroxyalkyl celluloses (for example, hydroxypropyl cellulose or hydroxypropyl methyl cellulose), polyvinyl pyrrolidone or methacrylic acid based polymers. They can be used from an aqueous or non-aqueous medium, as appropriate. Maltodextrin is particularly preferred.

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5

Particles with an intermediate coating in which cefuroxime axetil is present in a concentration of 30-10 wt.%, For example, 20 wt.%, Can be used for coating

lipid.

The lipid-coated particles of the present invention preferably contain 5-90%, more preferably 5-50%, and even more preferably 5 or 10 to 30 wt.% Cefuroxime axetil.

If cefuroxime axetil is a lipid coating of an intermediate coated particle, then preferably

content of cefuroxime axetil May 5-15. % if no intermediate coating is used, then the lipid-coated particles contain 10-30% by weight of cefuroxime axetil.

Typically, particles provided with an integral lipid coating to mask the bitter taste of cefuroxime axetil may have a diameter of less than 250 microns. Thus, coated particles having a diameter of 1-250 microns are preferred. The size of the coated particles is an important factor in terms of the bioavailability of cefuroxime axetil and the acceptability of such products for ingestion, since the particles

n with an average diameter of more than 250 microns give an undesirable sandy taste. The pharmaceutical products of the present invention thus take the form of coated particles with an average diameter of less than 100 microns, i.e. from 20 to 100

microns or more precisely 30-60 microns. It is convenient to apply whole lipid coatings on the particles prior to coating, having an average diameter of less than 80 microns, e.g. 50-60 microns. For example, amorphous cefuroxime axetil can be obtained in the form of hollow microspheres with an average diameter of 5-50 microns by spray-drying method, as described in UK Patent No. 2,127,401.

The coated particles of the present invention can be obtained by spraying a dispersion of cefuroxime axetil particles in a molten lipid and cooling the coated particles thus obtained, and this method is another distinguishing feature of the present invention. Such a dispersion can be obtained by adding cefuroxime acceleil particles and a molten lipid or mixture of lipids, or else by mixing the ingredients of the dispersion in a solid state, followed by fusion of the lipid or mixture of lipids.

Cefuroxime axetil particles can be dispersed in a molten lipid,

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using conventional devices, such as a high shear mixer. The temperature of the molten lipid is obviously 10–20 ° С higher than its melting temperature.

The preferred dispersed for the preparation of coated lipid particles of cefuroxime acetyl particles in a mixture of stearic acid and palmitic acid is in a weight ratio of (3: 7) to (7; 3), preferably in a weight ratio of 1: 1, The amount of cefuroxime is axitil in the dispersion x for preparing the lipid-coated particles of the present invention is / is calculated based on the required amount of cefuroxime axetil in the coated particle as described above. The dispersion is sprayed with enium and, upon cooling, particles of cefuroxime axetil coated with a lipid are obtained. Suitable equipment includes conventional atomizers such as a rotary atomizer, high pressure nozzles, pneumatic nozzles and ultrasonic nozzles.

It is especially convenient to use a pneumatic nozzle, in particular, a spray gun with a / liquid-liquid internal or external mixing pneumatic nozzle installed in a standard device for spray drying-cooling. A suitable internal: two-fluid mixing nozzle is described, for example, in UK Patent No. 1412133.

In a nebulization method using an atomizer with an internal two-fluid mixing nozzle, which is the preferred feature of the present invention, the molten lipid dispersion of cefuroxime axetil is typically fed to the atomizer head at a temperature of 60-80 ° C. preferably 65-5 ° C, the exact temperature being dependent on the particular lipid to be used. The spray gas supplied to the nozzle may be air or an inert gas such as nitrogen. The temperature of this gas is 60-90 ° C, preferably 70-55 ° C, and the exact temperature depends on the specific lipid material used.

We have found that during the coating process, it is preferable to emphasize the temperature of the molten dispersion 10-20 ° C above the melting temperature of the lipid or mixture of lipids used to obtain the dispersion having the viscosity desired for spraying. The spray pressure is adjusted to obtain- / coated coated particles of a preferred size, as described above.

The coated particles can be cured and collected by known methods. The coated particles can be cured by feeding a stream of cold air or 5 preferably dry nitrogen into the spray chamber / at a temperature of 0-30 ° C, preferably until the curing process is completed. The resulting product can be collected using a cyclone separator,

0 dust filter or by gravity.

If cefuroxime axetil is coated with an intermediate coating for dispersion in a lipid material, then the material

5 for intermediate coating can be applied to Schefuroxime axetil using conventional techniques, for example, spray coating using a fluidized bed granulator, a machine

0 for applying a centrifuge type fluidized bed coating or spray dryer, or coating with a rotary granulator.

In the preparation of lipid-coated particles using the above-described method, the concentration of the pre-coating of cefuroxime axetil in the molten dispersion is usually May 20-80. %, better 35-65 wt.%. Thus lipid

0 coating comprises 20-80 wt.%, Preferably 35-65 wt.% Of the coated particles of the present invention, which are obtained from cefuroxime axetil with an intermediate coating.

5 The invention is illustrated by the following examples.

The cefuroxime axetil used in the examples is a highly purified melt dried

0 amorphous material obtained as described in UK patent No. 2127401 and having an average particle diameter of 5-50 microns. Revel A is an industrial food grade of stearic acid, Hayfek is an industrial grade of stearic acid, Dinasan 112-glyceryltrilaurate and Dinasan 114-glyceryltrimyristate. Sang A, Hayfek. Dinasan 112 and 114 are trademarks.

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HRV stearic acid is defined as a mixture of fatty acids, mainly stearic and palmitic acids, in the British Pharmaceutical Codex (HRC)

5 (1973). B. Nat. FormuleryXV. 1980, USA US stearic acid is defined as containing not less than 40% stearic acid, not less than 40% palmitic acid and not less than 90% stearic and palmitic acid.

Granulometric measurements for examples 1-3 were performed using optical microscopy, a Coulter counter and laser scattering using the following methods:

1. Optical microscopy.

A small sample of the lipid-coated material was suspended on a glass slide in a silicone fluid and the particles were examined and counted at a magnification of 100 using a microscope.

Two slides were prepared for each serving and nine fields were counted on one glass. Particle size was determined in accordance with a grid of filaments of the UK standard (BS 3406, 1961) and distributed over the ranges 60 μm to 7.5 μm. A numerical count in each size range was recorded and used to calculate the volume mean diameter (VMD) using the following formula:

m

Z N (xi) Xf 1 1

SKxoX3.

Nxi is the number in this size range. Xi is the midpoint of the size range.

2. Coulter counter.

A small sample of the lipid-coated material was suspended in a Coulter dispersant on a glass slide. An amount of this dispersed sample was added to a Coulter meter measuring beaker containing a 1% solution of sodium chloride in distilled water, filtered through a 0.45 μm Milllpore filter, until the concentration index on the Coulter meter (model TA 11) was 5 -10%. The contents of the beaker were then sonicated for 30 minutes, placed in a Coulter counter, and stirred for 1 minute until counting. A number of particle counts were carried out over a range of size ranges from 8.0 microns to 128.0 microns. This count was repeated after four minutes of stirring.

The average of one minute and four minute samples was calculated for each size range and used to calculate VMD (formula described in method 1).

The measurement was repeated from the start of sample preparation for a minimum of five separate samples in a batch. Five values were averaged to obtain one compound mean.

Unless otherwise specified, all references in the description to average diameters are based on the Coulter counter method. 3. Laser scattering

A 5 mg sample of the lipid-coated material was introduced into 5 ml of 0.25% Tween 80 in distilled water and subjected to acoustic treatment for 60 s. The sample ampoule was inverted twice for

stirring the contents and then the sample was added dropwise to the measuring cell of the Malvern 3600 E-type classifier until a dimming of 0.2 beam was obtained. The readings were taken after one minute and

four minutes stirring in a cell.

The VMD value for each sample was calculated. In each series, at least five samples were measured and obtained

difficult average.

Example 1. Prepare a dispersion of amorphous cefuroxime axetil (150 g) in stearic acid powder In PC (850 g), melt the lipid, raising the temperature

molten lipid to a temperature of about 15 ° C above its melting point and cefuroxime axetil was added with stirring.

The molten lipid / cefuroxime axetil dispersion is introduced into the spray dryer / crystallizer unit using a peristaltic pump and sprayers using an external two-stage mixing fluid nozzle

(nozzle outlet size 2.54 mm / fluid hole) and 3.81-4.57 mm (annular liquid spray hole) at an air temperature of 65-70 ° C and a spray pressure of 345 kPa (50

psi inch). The product was cooled using a stream of air supplied to the spray chamber at ambient temperature and the cured product was collected in a cyclone separator.

Example 2. Dispersion of amorphous cefuroxime axetil (150 g) in stearic acid powder. PC (850 g) is obtained from a dry mixture of ingredients, melt the lipid and maintain the temperature at 15 ° C.

above the melting point of the lipid.

The molten lipid / cefuroxime axetil dispersion was pumped into a spray dryer / crystallizer at a rate of 300-500 ml / min and sprayed using an internal mixing two-stage liquid nozzle (supplied by Delavan Limited, Vidneye, Cherish, catalog number 32163-1 and described in the description of British patent N

1412133) at an air temperature of 65-70 ° C

and a spray pressure of 276-345 kPa (40-50 psi) per square inch. The product is cooled using a stream of air supplied to the spray chamber at ambient temperature and the solidified product is collected by gravity.

Example 3. The dispersion of amorphous cefuroxime axetil in the powder of stearic acid HRV was obtained as in example 2.

The molten lipid / cefixime axetil dispersion is pumped to the spray dryer / crystallizer unit by a gear pump and sprayed using an external mixing two-stage liquid nozzle (2.0 mm hole) at a temperature of 75 ° C and a spray pressure of 310 kPa (45 psi). PG, the product is cooled using a stream of air supplied to the spray chamber at ambient temperature and the cured product is collected in a cyclone separator

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pa te (

For batches of material obtained in accordance with the methods described in Examples 1-3, the following particle sizes were obtained (see Table 1).

EXAMPLE 4 A dry mixture of cefuroxime aksetil (124 g) and HRV stearic acid powder (676t) is heated at 68 ° C while stirring to melt the lipid and form a suspension. The molten lipid / cefuroxime axetil dispersion is introduced into the spray cooling chamber at a rate of 400 ml / min, supplying pressure to the melt chamber. Suspension: Dust using an internal blending two-stage liquid / e nozzle. Example 2) at an air temperature of 78 ° C 380 kPa (55 psi). The pfduct is cooled by a stream of air supplied to the spray chamber and the rejected product is collected using

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The average particle diameter by volume (Coultere counter) is 51 microns. The content of cefueoxime axetil is 15.4%.

EXAMPLE 5 A dispersion for lipid digestion is prepared by melt of a lipid, raising the temperature of the molten lipid to a temperature 15 ° C above its melting point and adding the appropriate amount of cefuroxime acyl with stirring using a high shear mixer. The molten suspension of lipid / cefuroxime axetil is pumped into a conventional pump using a spray bottle / crystallizer at a spray chamber height of 1.82 m at a speed of 300 ml / min and sprayed using an external mixing liquid two-stage nozzle (as in example 1) at a spray pressure of 275-414 kPa (40-60 psi). The product is cooled: using a 5 stream of air supplied to the spray chamber at 7-11 °. The solid product is collected in a cyclone separator.

The following mixtures of cefuroxime axetil and various lipids are spray-cooled to obtain taste masking lipid-coated cefuroxime axetil particles. The diameters of the obtained particles were determined by optical microscopy using an image analyzer of 5 Quantimetry 970 (see Table 2).

The average particle diameter by the number of 7.32 microns (95% of the total number of particles obtained had a diameter of less than 21 microns).

The average particle diameter by volume of 47.1 0 microns.

Example 6. Maltodextrin-coated particles of cefuroxime axetil were obtained by dispersing small dextrin a (400 g), fragrances of ice cream with fruit (1 g) and starch-5 mala 1500 (25 g) in distilled water (up to 1 l) using high shear mixers. Cefuroxime axetil (100 g) was dispersed in this suspension using a high shear mixer and a suspension of 3: then dried by spraying using conventional spray drying methods. The product was collected in a cyclone separator.

The maltodextrin-coated cefurox-5 sim axetil was then coated with HRV stearic acid as described in Example 5.

Stearin powder

BPC acid May 60% 600 g

Covered with maltodext-0 rin cefuroxime axetil May 40. % 400 g

The average particle diameter of the number of 7.51 microns (95% of the total number of particles obtained had a diameter of less than 23 microns). 5Average particle diameter by volume 46.0

microns.

EXAMPLE 7 Using the methods described in Example 5, the following mixtures of cefuroxime .axetil and various lipids 0 are spray-cooled to obtain taste-masking lipid-coated cefuroxime axetil particles.

For any specialist in this field, it is completely obvious that there are practically no technological difficulties in the production of both larger and smaller particles than particles, the sizes of which are indicated in the examples - ultimately, the limitations are due to such

properties of the compositions, such as the ability to chew, while super-large particles create the sensation of grains of sand.

The general superiority of the antibiotic properties of cefuroxime axetil over the properties of penicillin antibiotics, in particular, over the properties of penamecillin, is quite understandable. With respect to the advantages of the inventive method, the applicant indicates that when dogs coated with penicillin compositions according to the invention Ns 1323161 are introduced into the body, their blood levels are reached, approximately 60-80% lower than the levels achieved by the introduction of finely ground penicillin and that, in the opinion of the vital, means a significant reduction or decrease in the possibility of absorption.

The applicant was tested on volunteers using either a fully dispersed cefuroxime axetil, i.e. a regular tablet coated with cefuroxime axetil, or an aqueous suspension of a composition in accordance with the present invention. The concentration of cefuroxime in the urine of the subjects was measured and the total amount of cefuroxime excreted was calculated and expressed as a fraction of the amount administered (equivalent to 250 mg of cefuroxime). Since cefuroxime is not metabolized in the body and therefore enters urine unchanged, the final percentage excreted is a good indicator of the amount of cefuroxime axetil. absorbed from the gastrointestinal tract due to oral administration. Thus, the applicant obtained the following results (see table 4).

This suggests, according to the inventor, that the composition of the present invention is approximately 70% more effective than conventional tablets coated with a film masking the taste and only approximately 20% less effective than the fully dispersed cefuroxime axetil (unpleasant in taste). ) The fact that effective taste masking can be achieved with such a slight weakening of the effect is the most valuable hallmark of the present invention and makes such compositions especially valuable in pediatric medicine, since children who might have difficulty swallowing capsules or tablets can easy to treat with aqueous suspensions

compositions. In fact, the recently published results of clinical comparative studies in the treatment of pediatric pharyngitis with penicillin V and cefuroximaxetil suspensions

show that these latter allow a more significant clinical bacteriological response to be achieved.

Claims (6)

1. A method of coating an antibiotic by dispersing particles of an antibiotic in molten wax, cooling with their subsequent isolation, characterized in that, with an increase in its absorption in the gastrointestinal tract, cefuroxime axetil in an amount of 5- or more is used as an antibiotic. 20% of the total mass of the dispersion, and one or a mixture of carboxylic acids of the general formula RCOOH, their glycerol esters and alcohols of the formula ROH, where these groups are selected from straight-chain Cg-Cs alkyl groups with a temperature of tanning 30-80 ° C, dispersion is carried out in an atomizer with a pneumatic nozzle at a temperature of 10-20 ° C above the melting point of the wax, resulting in particles with a diameter of 20-100 microns. 2. The method according to claim 1, characterized in that cefuroxime axetil is amorphous cefuroximaxetil. 3. The method of claim 1, wherein the antibiotic is spray dried cefuroximaxetil in the form of hollow microspheres. 4. The method according to claim 1, wherein the antibiotic is cefuroximaxetil, the average particle diameter of which is 5-50 microns. 5. The method according to nn. 1-4.OT, wherein the wax is a mixture of stearic and palmitic acids in a weight ratio of about 1: 1. 6. The method according to claim 1, characterized in that the dispersion is carried out in an atomizer of internal mixing with two nozzles for a fluid medium. Priority on points: 05/14/37 according to claims 1-3-3; 02/09/08 according to paragraphs 4 and 6. Table 1 Note: All particle sizes are expressed as; jVMD Ti number of measured samples. Stearic Acid Powder 2 Lots In PC85 May% 850 g cefuroxime axetil May 15% 150 g (| average particle diameter of 7.18 μm (95% of the total number of particles obtained had diameter less than 22 microns) Average particle diameter by volume 41.9 microns 6} Hayfek85 May% .850 g cefuroxime axetil May 15% 150 g 4 average particle diameter of 7.93 microns (95% of the total number of particles obtained had diameter less than 25 microns) The average particle diameter in volume of 47.5 microns Powder of stearic acid of HRV Dinasan 112 212.5 g 212.5 g 75.0 g May 42.5. % 42.5 May. % ; , May 15% fedny particle diameter by number; -c, 38, microns (95% of the total number of particles obtained had diameter less than 32 microns) Average particle diameter in volume 51.0 microns Dinasan 112 85 May% 426 g cefuroxime axetil May 15% 75 g 212.5 g 212.5 g 75.0 g hour Continuation of Table 3 Table4